Seminars in Cancer Biology

Publications in this journal

• Article: Gene expression profiling to dissect the complexity of cancer biology: pitfalls and promise.

  Eric Raspe, Charles Decraene, Geert Berx
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  ABSTRACT: Despite advances in chemotherapy, hormone therapy and radiotherapy, not all cancer patients respond favorably to treatment. However, progress in understanding the mechanisms of malignant diseases and the mode of action of therapies are opening opportunities to match treatment to specific patient subpopulations, paving the way for personalized medicine. In this context, high throughput technologies that have been developed to determine gene expression profiles potentially offer an effective tool for dissecting the biology of cancer pathologies, for identifying candidate molecules for the development of new drugs, and for identifying individual patients who are more likely to respond favorably to a given therapy. Here, we overview and discuss the robustness of the deployment of these technologies in these contexts. We conclude that while these technologies are useful for target identification, there are limitations to their use in understanding cancer biology and in routine clinical application.
  Seminars in Cancer Biology 03/2012; 22(3):250-60.
• Article: Tumor associated regulatory dendritic cells.

  Yang Ma, Galina V Shurin, Dmitriy W Gutkin, Michael R Shurin
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  ABSTRACT: Immune effector and regulatory cells in the tumor microenvironment are key factors in tumor development and progression as the pathogenesis of cancer vitally depends on the multifaceted interactions between various microenvironmental stimuli provided by tumor-associated immune cells. Immune regulatory cells participate in all stages of cancer development from the induction of genomic instability to the maintenance of intratumoral angiogenesis, proliferation and spreading of malignant cells, and formation of premetastatic niches in distal tissues. Dendritic cells in the tumor microenvironment serve as a double-edged sword and, in addition to initiating potent anti-tumor immune responses, may mediate genomic damage, support neovascularization, block anti-tumor immunity and stimulate cancerous cell growth and spreading. Regulatory dendritic cells in cancer may directly and indirectly maintain antigen-specific and non-specific T cell unresponsiveness by controlling T cell polarization, MDSC and Treg differentiation and activity, and affecting specific microenvironmental conditions in premalignant niches. Understanding the mechanisms involved in regulatory dendritic cell polarization and operation and revealing pharmacological means for harnessing these pathways will provide additional opportunities for modifying the tumor microenvironment and improving the efficacy of different therapeutic approaches to cancer.
  Seminars in Cancer Biology 03/2012; 22(4):298-306.
• Article: Tumor metabolism as modulator of immune response and tumor progression.

  Eva Gottfried, Marina Kreutz, Andreas Mackensen
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  ABSTRACT: About a century ago Otto Warburg observed that tumor cells exhibited increased glycolysis despite the presence of oxygen and stated this metabolic shift to glycolysis as the origin of cancer cell. In the meantime it has become clear, that the altered glucose metabolism is only one piece of the tumor metabolome puzzle. In addition, amino acid, lipid and adenosine metabolism are adapted to fulfill the tumors needs for energy and generation of building blocks such as lipids and nucleotides for new cell structures. The altered tumor metabolism leads to accumulation of specific metabolites in the tumor environment and creates a favorable milieu for tumor growth, progression and metastasis. These tumor-derived metabolites are important players in immune escape mechanisms beside other known factors such as cytokines, chemokines and growth factors. A variety of metabolites re-educate immune cells and prevent an effective immune response against tumor cells. Furthermore, tumor infiltrating immune cells support tumor growth by the secretion of cytokines, growth factors and other metabolic determinants. Hence, a complex interplay of tumor metabolites, cytokines and stromal factors is active in tumors and facilitates their establishment and growth. Pharmacological blockade of tumor metabolites could overcome some limitations of cancer treatment and rescue the endogenous immune response against tumor cells.
  Seminars in Cancer Biology 03/2012; 22(4):335-41.
• Article: New insights into chronic inflammation-induced immunosuppression.

  Julia Kanterman, Moshe Sade-Feldman, Michal Baniyash
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  ABSTRACT: Chronic inflammation is a common factor linking various pathologies that differ in their etiology and physiology such as cancer, autoimmune diseases, and infections. At a certain stage of each of these diseases, while the chronic inflammation proceeds, some key players of the immune system become immunosuppressed as natural killer (NK) cells and T cells. The suppressive environment induced during chronic inflammation is governed by a complex processes characterized by the accumulation and activation of immune suppressor cells, pro-inflammatory cytokines, chemokines, growth and angiogenic factors, and by the activation of several inflammatory signaling pathways mediated predominantly by NFκB and STAT3 transcription factors. A substantial body of evidence supports the notion that the development of a suppressive environment during chronic inflammation limits the success of immune-based and conventional therapies, skewing the balance in favor of a developing pathology. Thus, appropriate, well-designed and fine tuned immune interventions that could resolve inflammatory responses and associated immunosuppression could enhance disease regression and reinforce successful responses to a given therapy. This review describes the interrelationship between chronic inflammation and induced immunosuppression, and explains the current evidence linking inflammation and pathological processes, as found in cancer. We further highlight potential strategies, harnessing the immunosuppressive environment in treating autoimmune diseases and facilitating transplantation. In parallel, we emphasize the use of modalities to combat chronic inflammation-induced immunosuppression in cancer, to enhance the success of immune-based therapies leading to tumor regression. In both cases, the urgent necessity of identifying biomarkers for the evaluation of host immune status is discussed, with the goal of developing optimal personalized treatments.
  Seminars in Cancer Biology 02/2012; 22(4):307-18.
• Article: Concepts of metastasis in flux: the stromal progression model.

  Jonathan P Sleeman, Gerhard Christofori, Riccardo Fodde, John G Collard, Geert Berx, Charles Decraene, Curzio Rüegg
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  ABSTRACT: The ability of tumor cells to leave a primary tumor, to disseminate through the body, and to ultimately seed new secondary tumors is universally agreed to be the basis for metastasis formation. An accurate description of the cellular and molecular mechanisms that underlie this multistep process would greatly facilitate the rational development of therapies that effectively allow metastatic disease to be controlled and treated. A number of disparate and sometimes conflicting hypotheses and models have been suggested to explain various aspects of the process, and no single concept explains the mechanism of metastasis in its entirety or encompasses all observations and experimental findings. The exciting progress made in metastasis research in recent years has refined existing ideas, as well as giving rise to new ones. In this review we survey some of the main theories that currently exist in the field, and show that significant convergence is emerging, allowing a synthesis of several models to give a more comprehensive overview of the process of metastasis. As a result we postulate a stromal progression model of metastasis. In this model, progressive modification of the tumor microenvironment is equally as important as genetic and epigenetic changes in tumor cells during primary tumor progression. Mutual regulatory interactions between stroma and tumor cells modify the stemness of the cells that drive tumor growth, in a manner that involves epithelial-mesenchymal and mesenchymal-epithelial-like transitions. Similar interactions need to be recapitulated at secondary sites for metastases to grow. Early disseminating tumor cells can progress at the secondary site in parallel to the primary tumor, both in terms of genetic changes, as well as progressive development of a metastatic stroma. Although this model brings together many ideas in the field, there remain nevertheless a number of major open questions, underscoring the need for further research to fully understand metastasis, and thereby identify new and effective ways of treating metastatic disease.
  Seminars in Cancer Biology 02/2012; 22(3):174-86.
• Article: Building the niche: the role of the S100 proteins in metastatic growth.

  Eugene Lukanidin, Jonathan P Sleeman
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  ABSTRACT: Communication between cancer cells and stromal cells, often mediated by extracellular molecules in the tumor microenvironment, plays a central role in tumorigenesis and metastasis. The establishment of a pro-inflammatory milieu is increasingly recognized as an important consequence of these interactions. The family of S100 Ca2+-binding proteins has been implicated in many aspects of the interaction between cancer cells and stromal cells, and contributes to the formation of an inflammatory tumor microenvironment. Focusing on S100A4, S100A8 and S100A9, in this review we discuss the role these proteins play in primary tumors and in the development of metastases, in particular during the formation of pre-metastatic niches.
  Seminars in Cancer Biology 02/2012; 22(3):216-25.
• Article: Recent advances on the role of tumor exosomes in immunosuppression and disease progression.

  Paola Filipazzi, Maja Bürdek, Antonello Villa, Licia Rivoltini, Veronica Huber
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  ABSTRACT: Exosomes are endosomal-derived nanovesicles released by most cells types, including tumor cells, and principally involved in intercellular communication in physiology and disease. Tumor exosomes are gaining increasing interest in medicine and oncology as efficient tools for the delivery of defined signals. Representing the acellular replicas of tumor cells, they contain a great variety of bioactive molecules, such as proteins, RNA, miRNA and DNA. Their great ability to recirculate in body fluids and their structure allow them to transport their cargo to distant targets. Major studies have shown that tumor exosomes convey information not only between tumor cells but also to other cell types, including different immune cell components. There is increasing evidence that these nanovesicles may contribute to cancer progression by influencing different immune cell types, likely blunting specific T cell immunity and skewing innate immune cells toward a pro-tumorigenic phenotype. Because of this function and the additional property to deliver molecular signals modulating neoangiogenesis and stroma remodeling, tumor exosomes are believed to play a role in tumor progression by favoring metastatic niche onset. This review outlines the recent knowledge on immune suppressive mechanisms mediated by tumor exosomes. We will discuss our view on the role of these nanovesicular structures in cancer progression and how their presence could interfere with cancer therapy.
  Seminars in Cancer Biology 02/2012; 22(4):342-9.
• Article: Differentiation and gene expression profile of tumor-associated macrophages.

  Astrid Schmieder, Julia Michel, Kathrin Schönhaar, Sergij Goerdt, Kai Schledzewski
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  ABSTRACT: Tumor microenvironment is composed of proliferating neoplastic cells, a vascular network of endothelial cells, extra cellular matrix produced by fibroblasts, cellular compartments of adaptive immunity like lymphocytes and dendritic cells as well as cells of innate immunity, e.g., natural killer cells and macrophages. Many pre-clinical and clinical studies demonstrate an inversed correlation between macrophage infiltrate and patients' prognosis indicating a macrophage supporting role for tumor progression as producers of growth and angiogenic factors and as regulators of tissue remodelling. Based on in vitro models, macrophages have been classified in pro-inflammatory, classically activated macrophages (M1; stimulated by IFN-γ or LPS) and anti-inflammatory, alternatively activated macrophages (M2; stimulated by either IL-4/IL-13, IL-1β/LPS in combination with immune complexes or by IL-10/TGFβ/glucocorticoids). Tumor escape has been linked with a switch from M1 activation in the early tumor initiation process towards M2-like phenotype during tumor progression, a process that highlights the heterogeneity and plasticity of macrophage activation and which offers a possible therapeutic target directed against reversing the TAM phenotype in the tumor. Here, we review different tumor-environmental stimuli and signalling cascades involved in this switch in differentiation and the so connected gene regulation in TAMs. In addition, therapeutic applications deducted from this differentiation and gene regulatory processes are presented. Data from pre-clinical as well as clinical studies clearly support the notion, that TAMs are excellent novel therapeutic targets for the fight against cancer.
  Seminars in Cancer Biology 02/2012; 22(4):289-97.
• Article: Telomeres and the nucleus.

  Clara Lopes Novo, J Arturo Londoño-Vallejo
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  ABSTRACT: Telomeres are crucial for the maintenance of genome stability through "capping" of chromosome ends to prevent their recognition as double-strand breaks, thus avoiding end-to-end fusions or illegitimate recombination [1-3]. Similar to other genomic regions, telomeres participate to the nuclear architecture while being highly mobile. The interaction of telomeres with nuclear domains or compartments greatly differs not only between organisms but also between cells within the same organism. It is also expected that biological processes like replication, repair or telomere elongation impact the distribution of chromosome extremities within the nucleus, as they probably do with other regions of the genome. Pathological processes such as cancer induce profound changes in the nuclear architecture, which also affects telomere dynamics and spatial organization. Here we will expose our present knowledge on the relationship between telomeres and nuclear architecture and on how this relationship is affected by normal or abnormal telomere metabolisms.
  Seminars in Cancer Biology 02/2012;
• Article: Cancer immunotherapy: are we there yet?

  Benjamin Sredni, Dan L Longo
  Seminars in Cancer Biology 02/2012; 22(1):1-2.
• Article: Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression.

  Suzanne Ostrand-Rosenberg, Pratima Sinha, Daniel W Beury, Virginia K Clements
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  ABSTRACT: The tumor microenvironment is a complex milieu of tumor and host cells. Host cells can include tumor-reactive T cells capable of killing tumor cells. However, more frequently the tumor and host components interact to generate a highly immune suppressive environment that frustrates T cell cytotoxicity and promotes tumor progression through a variety of immune and non-immune mechanisms. Myeloid-derived suppressor cells (MDSC) are a major host component contributing to the immune suppressive environment. In addition to their inherent immune suppressive function, MDSC amplify the immune suppressive activity of macrophages and dendritic cells via cross-talk. This article will review the cell-cell interactions used by MDSC to inhibit anti-tumor immunity and promote progression, and the role of inflammation in promoting cross-talk between MDSC and other cells in the tumor microenvironment.
  Seminars in Cancer Biology 02/2012; 22(4):275-81.
• Article: Monoclonal antibodies for the treatment of cancer.

  Casey W Shuptrine, Rishi Surana, Louis M Weiner
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  ABSTRACT: Over the past decade, the clinical utility of monoclonal antibodies has been realized and antibodies are now a mainstay for the treatment of cancer. Antibodies have the unique capacity to target and kill tumor cells while simultaneously activating immune effectors to kill tumor cells through the complement cascade or antibody-dependent cellular cytotoxicity (ADCC). This multifaceted mechanism of action combined with target specificity underlies the capacity of antibodies to elicit anti-tumor responses while minimizing the frequency and magnitude of adverse events. This review will focus on mechanisms of action, clinical applications and putative mechanisms of resistance to monoclonal antibody therapy in the context of cancer.
  Seminars in Cancer Biology 02/2012; 22(1):3-13.
• Article: Neoplastic "Black Ops": cancer's subversive tactics in overcoming host defenses.

  Arya Biragyn, Dan L Longo
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  ABSTRACT: Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross-talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack.
  Seminars in Cancer Biology 02/2012; 22(1):50-9.
• Article: Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells.

  Srinivas Nagaraj, Dmitry I Gabrilovich
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  ABSTRACT: Myeloid derived suppressor cells play a critical role in T cell suppression in cancer. Here, we discuss the mechanisms of how MDSC suppress CD4(+) or CD8(+) T cells in an antigen dependent or non-dependent manner.
  Seminars in Cancer Biology 01/2012; 22(4):282-8.
• Article: Cancer biology and the nuclear envelope: A convoluted relationship.

  Jose I de Las Heras, Dzmitry G Batrakou, Eric C Schirmer
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  ABSTRACT: Although its properties have long been used for both typing and prognosis of various tumors, the nuclear envelope (NE) itself and its potential roles in tumorigenesis are only beginning to be understood. Historically viewed as merely a protective barrier, the nuclear envelope is now linked to a wide range of functions. Nuclear membrane proteins connect the nucleus to the cytoskeleton on one side and to chromatin on the other. Several newly identified nuclear envelope functions associated with these connections intersect with cancer pathways. For example, the nuclear envelope could affect genome stability by tethering chromatin. Some nuclear envelope proteins affect cell cycle regulation by directly binding to the master regulator pRb, others by interacting with TGF-ß and Smad signaling cascades, and others by affecting the mitotic spindle. Finally, the NE directly affects cytoskeletal organization and can also influence cell migration in metastasis. In this review we discuss the link between the nuclear envelope and cellular defects that are common in cancer cells, and we show that NE proteins are often aberrantly expressed in tumors. The NE represents a potential reservoir of diagnostic and prognostic markers in cancer.
  Seminars in Cancer Biology 01/2012;
• Article: Transcription factories, chromatin loops, and the dysregulation of gene expression in malignancy.

  Binwei Deng, Svitlana Melnik, Peter R Cook
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  ABSTRACT: Pathologists recognize and classify cancers according to nuclear morphology, but there remains little scientific explanation of why malignant nuclei possess their characteristic features, or how those features are related to dysregulated function. This essay will discuss a basic structure-function axis that connects one central architectural motif in the nucleus-the chromatin loop-to the vital nuclear function of transcription. The loop is attached to a "transcription factory" through components of the transcription machinery (either polymerases or transcriptional activators/repressors), and the position of a gene within a loop determines how often that gene is transcribed. Then, dysregulated transcription is tightly coupled to alterations in structure, and vice versa. We also speculate on how the experimental approaches being used to analyze loops and factories might be applied to study the problems of tumour initiation and progression.
  Seminars in Cancer Biology 01/2012;
• Article: MicroRNAs and STAT interplay.

  Gary Kohanbash, Hideho Okada
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  ABSTRACT: MicroRNA (miR) are emerging as important gene expression regulators often involved in a variety of pathogenesis such as cancers and autoimmunity. Signal transducers and activators of transcription (STAT) proteins are the principle signaling proteins for many cytokines and growth factors, thereby play a critical role in regulating immune cell homeostasis, differentiation and cellular functions. In this review, we discuss recent advances in the field demonstrating active interactions between STATs and miRs, with our primary focus on the promotion and inhibition of immune cells and cancer. Additionally, we review the reciprocal regulations between STATs and miR, and discuss how we can use this knowledge in the context of diseases. For example, recent findings related to STAT1 and miR-155 support the presence of a positive feedback loop of miR-155 and STAT1 in response to inflammatory signals or infection. STAT3 is known to play critical roles in tumorigenesis and cancer-induced immunosuppression. There is a growing body of evidence demonstrating that STAT3 directly activates miR-21, one of miRs that promote cancer cell survival and proliferation. While some miRs directly regulate STATs, there are findings demonstrating indirect STAT regulation by miRs also mediate important biological mechanisms. Therefore, further research is warranted to elucidate significant contributions made by direct and indirect miR-STAT mechanisms. As we learn more about miR pathways, we gain the opportunity to manipulate them in cancer cells to slow down growth or increase their susceptibility anti-tumor immunity.
  Seminars in Cancer Biology 12/2011; 22(1):70-5.
• Article: Genetically modulating T-cell function to target cancer.

  Efrat Merhavi-Shoham, Astar Haga-Friedman, Cyrille J Cohen
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  ABSTRACT: The adoptive transfer of tumor-specific T-lymphocytes holds promise for the treatment of metastatic cancer. Genetic modulation of T-lymphocytes using TCR transfer with tumor-specific TCR genes is an attractive strategy to generate anti-tumor response, especially against large solid tumors. Recently, several clinical trials have demonstrated the therapeutic potential of this approach which lead to impressive tumor regression in cancer patients. Still, several factors may hinder the clinical benefit of this approach, such as the type of cells to modulate, the vector configuration or the safety of the procedure. In the present review we will aim at giving an overview of the recent developments related to the immune modulation of the anti-tumor adaptive response using genetically engineered lymphocytes and will also elaborate the development of other genetic modifications to enhance their anti-tumor immune response.
  Seminars in Cancer Biology 12/2011; 22(1):14-22.
• Article: Cancer-related inflammation: common themes and therapeutic opportunities.

  Frances R Balkwill, Alberto Mantovani
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  ABSTRACT: Inflammatory cells and mediators are an essential component of the tumor microenvironment. Inflammatory circuits can differ considerably in different tumors in terms of cellular and cytokine networks and molecular drivers. However, macrophages are a common and fundamental component of cancer promoting inflammation. Drivers of macrophage functional orientation include tumor cells, cancer-associated fibroblasts, T cells and B cells. Dissection of the diversity of cancer-related inflammation is instrumental to the design of therapeutic approaches that target cancer-related inflammation.
  Seminars in Cancer Biology 12/2011; 22(1):33-40.